High drug load mesalazine sachet

ABSTRACT

The present invention is directed to a high drug formulation having desirable properties in terms of ease of manufacture and visual appearance as well as a sachet for the formulation.

FIELD OF THE INVENTION

The present invention concerns a pharmaceutical formulation comprising ahigh load of active drug.

In particular, it concerns a particulate pharmaceutical formulationcomprising a high load (i.e. with high weight % active drug) of5-aminosalicylic acid (5-ASA, mesalamine, mesalazine) for oraladministration as well as a method for producing it and a sachet for theformulation.

The present writ claims priority from the Danish patent application PA2003 00612, The European patent application EP 03388023, and the U.S.provisional patent application 60/464649.

TECHNICAL BACKGROUND

Oral pharmaceutical formulations comprising mesalazine are known, whichare either tablets or granulate. The granulate may be packed in sachets.For the purposes of the present invention a “sachet” will refer to anenvelope or bag for a granulate, while “granulate” refers to particles,granulate or spheronised particles.

Presently, tablets containing 250 or 500 mg mesalazine are known.Tablets of 250 mg typically weigh about 540 mg, i.e. they have a drugload of (250/540)% by weight=46% by weight. Tablets containing up to 84%by weight mesalazine have been described in the patent application WO00/44353 with the title “Pharmazeutische Zusammensetzungen”.

For sachets, Dr. Falk Pharma has launched a product which claims tocontain 500 mg mesalazine in a 930 mg sachet, corresponding to a drugload of 54% by weight.

Presently up to 4 g of mesalazine are often prescribed for the dailytreatment of intestinal bowel diseases, such as Crohn's disease andUlcerative Colitis.

If 4 g of mesalazine is administered in 250 mg tablets, the patientneeds to swallow 16 tablets a day. Alternatively, 500 mg tablets may beadministered, but with a drug load in the 50% range, the tablets willweigh about 1 g each, which many patients find rather large to swallow.

There exists a need to provide a product which allows administeringlarge daily doses of drug without adversely affecting patientcompliance.

Methods for manufacturing oral pharmaceutical formulations comprisingmesalazine on an industrial scale are known. However, known methods ofmanufacture necessitate a high number of production steps to achieve aproduct having desirable release characteristics. This leads tocumbersome and expensive manufacture.

DISCLOSURE OF THE INVENTION

These problems and others mentioned below are addressed by aspects ofthe invention.

According to an aspect, the present invention concerns an oralpharmaceutical formulation, preferably for a sachet, comprising anamount of mesalazine selected among the group consisting of 55; 60; 65;70; 75; 80; 85; 90; 92; 94 and 96% by weight. According to a preferredaspect, the formulation comprises 92-98, preferably 94-96,% by weightmesalazine.

These aspects provide a high load pharmaceutical composition.

For the purposes of the present invention “mesalazine” also encompassespharmaceutically acceptable salts and esters thereof, such as thosementioned in WO 97/23199 p. 15, 1. 17-p. 6, 1. 12, as well as prodrugs,such as balsalazide.

The formulation is preferably in the form of a particulate material,e.g. granulate, spheres, pellets, particles, preferably granulate.

According to an aspect, the present invention concerns a pharmaceuticalformulation further comprising a pharmaceutically acceptable binder,preferably Povidone, in an amount selected among the group consisting of1; 2; 3; 4; 5; 6; 7; 8; 9; 10; and 12% by weight. According to apreferred aspect, the formulation comprises 1-10, preferably 2-8; morepreferred 3-7; preferably 4-6; most preferred 5% by weight Povidone.

The pharmaceutically acceptable binder may comprise any acceptablebinder such as Acacia, Gelatin, Hydroxypropyl cellulose,Hydroxypropylmethyl cellulose, Methylcellulose, Polyetylene glycol(PEG), Povidone, Sucrose, Starch or a mixture of any of these. Povidone(Polyvinylpyrrolidone, PVP) is preferred.

According to an aspect, the present invention concerns a pharmaceuticalformulation further comprising a coating.

The coating should preferably comprise a release modifying agent, suchas ethylcellulose, carnauba wax, shellac or a mixture of any of these.Ethylcellulose is preferred.

The selected coating depends inter alia on the desired release pattern.It may be chosen from rate limiting barrier materials, e.g. enteric ordelayed coating material, such as polymethacrylate, commerciallyavailable in the form of Eudragits, e.g. Eudragit NE 40 D or Eudragit L100. When a semi-permeable polymer is used, ethyl cellulose is the mostpreferred coating.

According to an aspect, the formulation is a modified releaseformulation, preferably an extended release formulation.

According to an aspect, the formulation comprises a coating, the ratioof the weight of said coating to the weight of said mesalazine or saidpharmaceutically acceptable salt being selected among 0.1-10%; 0.3-7%;0.5-5%; 0.7-3%; 0.8-2%; and 0.9-1.5%. The amount of coating may beadjusted to reach the desired release profile. Very high amount ofcoating may impede the release of active ingredient.

According to an aspect, the present invention concerns a pharmaceuticalformulation essentially consisting of mesalazine, a pharmaceuticallyacceptable binder and a coating.

According to an aspect, the present invention concerns a pharmaceuticalformulation having in vitro release characteristics of mesalazine of atleast 40, 50, 60, 70, 80, or 90% released after 240 min, of the totalamount of mesalazine in the formulation, measured in a model systemusing a USP Paddle System 2 operated at 37° C. with stirring at 100 rpm.Usually a higher release is preferred in order to ensure effectiverelease in the intestines.

According to an aspect, the present invention concerns a pharmaceuticalformulation having in vitro release characteristics of mesalazine of

-   -   a) 5-25% released after 15 min;    -   b) 30-70%, preferably 40-60%, released after 90 min; and    -   c) 75-100% released after 240 min;        of the total amount of mesalazine in the formulation, measured        in a model system using a USP Paddle System 2 operated at 37° C.        with stirring at 100 rpm.

The dissolution parameters for the model system were: Dissolutionmedium: 1000 ml deaerated 0.1 M sodium phosphate buffer pH 7.5.

Apparatus: USP 23 Paddle method (Apparatus 2)

Shaft rotation speed: 100 rpm. 1 g sachets were used for experiments.

According to a first preferred aspect, the present invention concerns apharmaceutical formulation having a similarity factor f₂ above a numberselected from 25, 30, 35, 40, 45, 50, 55, 60, 65, and 70, as compared toa standard having the in vitro release characteristics of mesalazine of

-   -   a) 12% released after 15 min;    -   b) 50% released after 90 min; and    -   c) 85% released after 240 min;        as measured under the conditions listed above.

The similarity factor f₂ is defined as

$f_{2} = {50\;\log\left\{ {\left\lbrack {1 + {\left( {1/n} \right){\sum\limits_{t = 1}^{n}\left( {R_{t} - T_{t}} \right)^{2}}}} \right\rbrack^{- 0.5}*100} \right\}}$wherein n is the number of time points, R(t) is the mean percent activeingredient dissolved of the standard, and T(t) is mean percent activeingredient dissolved of the formulation according to the invention. Thesimilarity factor is usually considered satisfactory if in the range50-100, but may for the purposes of the present invention be evensmaller.

According to a second preferred aspect, the present invention concerns apharmaceutical formulation having a similarity factor f₂ above a numberselected from 25, 30, 35, 40, 45, 50, 55, 60, 65, and 70, as compared toa standard having the in vitro release characteristics of mesalazine of

-   -   d) 21% released after 15 min;    -   e) 68% released after 90 min; and    -   f) 94% released after 240 min;        as measured under the conditions listed above.

According to an aspect, the present invention concerns a pharmaceuticalformulation, wherein said pharmaceutical formulation is packed in asachet.

According to an aspect, the present invention concerns a method formanufacturing a granulate comprising the steps:

-   -   a) mixing mesalazine with granulation liquid;    -   b) obtaining granulate by granulating, compacting or extruding;    -   c) drying the granulate;    -   d) adjusting the size of the granulate as necessary; and    -   e) sieving the granulate as necessary;    -   characterised in the additional step of:    -   f) coating the granulate;    -   and optionally further:    -   g) sieving the coated granulate;    -   h) air purging the coated granulate.

According to an aspect, the present invention concerns a method, whereinthe coated granulate are packed in sachets.

Other suitable package forms are containers usually used for oralformulations.

This method provides a simple manufacturing method for pharmaceuticalformulations.

According to an aspect of the invention a pharmaceutical composition isprovided being produced without spheronization. The composition is thusobtainable without spheronization. Thereby the need for a spheronizationaid is eliminated, allowing the pharmaceutical composition to have ahigh drug load.

Spheronization has been used to obtain a reproducible product on anindustrial scale, the product being visually appealing and easy toadminister, leading to high patient compliance.

It has until the present invention been considered neccessary tospheronise mesalazine drugs in order to obtain a visually appealing andeasily administrable sachet product. Spheronisation implies the use of aspheronization aid or enhancer, such as microcrystalline cellulose. Thepresence of a spheronization aid leads to drug loads lower thanobtainable with the present invention.

There exists a demand for a dust-free high load pharmaceuticalcomposition. A pharmaceutical formulation meeting these criteria isachieved according to an aspect of the invention without spheronization.Such composition may be provided by obtaining a granulate. A granulatemay be obtained by granulating, compacting or extruding, in order toachieve a product which is visually appealing to a person to whom saidpharmaceutical formulation is administered. Compacting may be performede.g. by roll compacting. The granulate is preferably obtained byextruding.

According to a certain preferred aspect of the present invention, thepharmaceutical composition is obtained according to co-pending patentapplication PCT/DK01/00677 with the title “Method for the preparation ofa pharmaceutical composition comprising 5-aminosalicylic acid for use intreatment of Ulcerative Colitis and Crohn's Disease”, withmodifications. The modifications comprise that the coating should beadapted according to the present invention, and that after coating,sieving and nitrogen purging, the obtained granulate are packed insachets, without the need for further excipients (cf. Example 3 and FIG.4 of said application). It is especially preferred that the granulationliquid comprises at least 50%, more preferred 60%, preferably 70%, morepreferred 80%, preferably 85%, more preferred 90%, w/w water.

According to an aspect, the present invention concerns the method,wherein the granulation liquid consists of Povidone dissolved in water.

According to an aspect, the present invention concerns the method,wherein said drying step c) is performed in a fluid bed dryer.

According to an aspect, the present invention concerns the method,wherein said adjusting of size step d) is performed by milling.

According to an aspect, the present invention concerns the method,wherein the sieving step e) is performed by selecting granulate passinga 1.8 mm sieve, but not passing a 0.5 mm sieve.

Other suitable sieves may be used, e.g. having sizes selected among thegroup consisting of 4.0; 3.15; 2.5; 2.0; 1.8; 1.6; 1.4; 1.25; 1.18; 1.0;0.9; 0.8; 0.71; 0.6; 0.5 and 0.4 mm for selecting desired granulate. Thesieves may be chosen to determine upper and/or lower limits of particlesizes.

According to another aspect, the resulting granules, after being milled,have a particle size distribution measured by sieve analysis where themain fraction is from 850 μm to 1000 μm. The holes in an extruder may bevaried in order to obtain the desired particle size. According to anaspect, more than 75%, preferably more than 85% and most preferably morethan 90% of the granules have a particle size from 850 μm to 1000 μm.

According to an aspect, the present invention concerns the method,wherein the coating step f) is performed with ethylcellulose.

According to an aspect, the present invention concerns the method,wherein the coating step f) is performed by spraying with an amount ofcoating material, adjusted according to the specific surface area, to bein the range 0.09-0.17 mg/cm², preferably 0.11-0.15 mg/cm², morepreferred 0.12-0.14 mg/cm², followed by drying. These amounts have beenfound suitable for coating with ethylcellulose.

It has been discovered that the desired release profile may be obtainedby adjusting the amount of coating material used according to thespecific surface area.

The specific surface area may be measured by permeametry according to“Evaluation of a permeametry technique for surface area measurement ofcoarse particulate materials, International Journal of Pharmaceutics,Eriksson et al., 1990, 63, p. 189-199”.

Granulate obtained according to co-pending patent applicationPCT/DK01/00677, preferably with modifications according to the presentinvention, is especially preferred, as is has a smooth surfacefacilitating measurement of specific surface area as well as subsequentcoating.

In order to be able to determine the amount of coating that has to beapplied to the granules the surface area is measured. Based on themeasured correlation between the amount of coating per surface area andthe dissolution rate profile, the amount of coating needed can bepredicted from the measured surface area of the granules. The amount isadjusted by trial and error, as it depends on the exact conditions used,e.g. apparatus and excipients.

According to an aspect, the present invention concerns the method,wherein the sieving step g) is performed on a rotation sieve, preferablywith a mesh size of 2.5 mm, in order to obtain coated granulate of asize smaller than or equal to 2.5 mm.

Other suitable sieves may be used, e.g. having sizes selected among thegroup consisting of 4.0; 3.15; 2.5; 2.0; 1.8; 1.6; 1.4; 1.25; 1.18; 1.0;0.9; 0.8; 0.71; 0.6; 0.5 and 0.4 mm for selecting desired size of coatedgranulate.

According to an aspect, the present invention concerns a pharmaceuticalformulation, preferably according to any of the aspects mentioned above,obtainable according to the method.

According to an aspect, the invention concerns pharmaceuticalformulations for medical use.

According to an aspect, the present invention concerns the use ofmesalazine for the manufacture of a pharmaceutical formulation accordingto the invention, comprising a total amount of mesalazine chosen amongthe group consisting of 0.5 g; 1.0 g; 1.5 g; 2 g; 3 g; 4 g; 5 g; 6 g; 8g; and 10 g.

According to an aspect, the present invention concerns the use, whereinthe medicament is for the treatment of intestinal bowel disease (IBD),preferably Crohns's Disease or Ulcerative Colitis.

The formulations according to the invention are suitable for thetreatment of IBD.

According to an aspect the invention concerns a method for treatment ofIBD, wherein the formulation according to the invention is administeredto the patient, preferably 1, 2, 3 or 4 times daily.

The formulations according to the invention may be packed in differentcontainers which allow administering to patients, such as capsules,blister packages, dispensers, glass or plastic containers, and sachets.

According to an aspect, the present invention concerns a sachet for apharmaceutical formulation, preferably according to the invention.

The present sachet may be used for any pharmaceutical formulation, butis especially suitable for storing pharmaceuticals comprising sensitivecompounds such as mesalazine.

According to an aspect, the present invention concerns a sachet,comprising the layers:

i) paper;

ii) bonding layer, preferably an adhesive such as polyethylene;

iii) barrier layer, preferably aluminium foil; and

iv) sealing layer, preferably low density polyethylene.

Mesalazine is sensitive to humidity, atmospheric air and/or light. Asachet for a product containing mesalazine should therefore preferablyprovide a barrier to humidity, atmospheric air and light. The sachetshould also be easy to open for a patient, preferably without the use ofadditional tools, such as scissors. It has been a problem to provide asachet with the necessary barrier properties without sacrificing thepossibility of tearing open the sachet with human fingers. Further,existing sachets tend to suffer from the build up of static electricity.Preferably, a sachet should be easy to manufacture, easy to fill, easyto empty, and have an appealing look to improve patient compliance.

This aspect provides a sachet giving long storage stability for apharmaceutical composition contained therein, e.g. where the activepharmaceutical ingredient is mesalazine. Further, the sachet is easy totear and static electricity is eliminated, providing for a sachet whichmay be emptied completely for its contents. The combination of thesachet and the oral formulation according to the present inventionprovides for little build up of static electricity.

According to an aspect, the present invention concerns the sachet,wherein the bonding layer ii) preferably has a weight per unit area of6-20 g/m², preferably 9-15 g/m², more preferred 12 g/m²; the barrierlayer iii) preferably has a thickness of 6-30 μm, more preferred 7-25μm, preferably 9-25 μm, more preferred 8-20 μm, preferably 9-15 μm, morepreferred 12 μm; and/or the sealing layer iv) preferably has a weightper unit area of 10-100 g/m², more preferred 15-75 g/m², preferably20-50 g/m², more preferably 30-40 g/m², most preferred 35 g/m².

The outer paper i) has in a preferred embodiment a weight per unit areaof 10-100 g/m², preferably 30-70 g/m², most preferred 50 g/m².

According to an aspect, the present invention concerns the use of thesachet for a pharmaceutical composition according to the invention.

The sachet has proven suitable for storing the pharmaceuticalcompositions according to the invention.

According to an aspect, the present invention concerns the use of thesachet for medical purposes.

According to an aspect of the present invention it is not limited to theuse of mesalazine as the active ingredient, but also relates to otheractive ingredients, such as the ingredients mentioned in WO 00/44353, p.12-16. Other low potent active ingredients are suitable for the presentinvention. Especially ibuprofen is envisioned as replacing mesalazine.

According to an aspect of the present invention further excipients maybe comprised in the composition according to the invention, such asfillers, disintegrants, pH adjusters, or surfactants. Such excipientsare well known from the literature, see e.g. WO 00/44353, p. 16-20, fora number of suitable excipients.

EXAMPLES

Unless otherwise stated, all percentages are in % by weight.

Example 1

A batch for the production of 180,000 sachets of prolonged releasegranules was provided as follows.

Constituents Quantity Specification Mesalazine  180 kg Ferring Povidone  9 kg Ph. Eur. Water, purified 33.3 kg** Ph. Eur. Ethylcellulose  1.9kg*** Ph. Eur. Acetone  188 kg** Ph. Eur. **Evaporates duringproduction. ***The amount of ethylcellulose was adjusted to ensure thedesired dissolution profile of the finished product. Ph. Eur. refers tothe current edition at the time of filing of the present application.

The manufacturing method follows closely the manufacturing methoddescribed in co-pending patent application PCT/DK01/00677, with someexceptions. The amount and type of ingredients is adjusted, and inparticular the amount of ethylcellulose is reduced to obtain the desireddissolution profile. In this example no tablets were made, so excipientsfor this purpose are not included, no dry blending is performed afterthe air purging, and no tableting performed. The granulate productresulting from the present process is therefore different from thetablet of said application.

The manufacturing process for the formulation can be divided into 9steps:

1. Preparation of granulation liquid

2. Granulation of Mesalazine with water and PVP

3. Extrusion

4. Fluid bed drying

5. Milling

6. Sieving

7. Coating

8. Sieving

9. Air purging

Equipment for the production Function NICA Extruder E220 ExtrusionRotostat T05 Blending NIRO Fluid bed dryer Drying Quadro Comil U10Milling Mogensen sieve Sieving Huttlin Kugelcoater HKC 400 CoatingProdima rotation sieve Sieving Purging unit Air purge

Step 1:

For one batch of granulation liquid water is filled into a Müller drum.The mixer is put into position and started. Polyvinylpyrrolidone (PVP)is slowly sprinkled onto the water and the mixer is allowed to run afixed time until all PVP is dissolved.

Step 2 and 3:

Mesalazine is placed in a vibrating Prodima hopper and by the use of aconveyor the mesalazine is transported up to a weight belt feeder dosingthe mesalazine into the continuous Niro line. In the first part of theNiro line the mesalazine and the water solution of PVP are mixed to awet mass before being transported into the extruder. After extrusion ofthe wet mass of mesalazine and PVP/water through a screen mesh 0.9 mm,the granules fall directly into the fluid bed dryer.

Step 4:

The fluid bed dryer is divided into two main sections. In the firstsection, the granules are dried on the surface to prevent them fromsticking together. In this section of the fluid bed, a random mixing ofthe granules takes place. After a certain residence time, the granulesare moved into the second part of the dryer where the actual dryingtakes place. In the second part of the dryer the granules are guided bythe use of the drying air through the dryer (special pattern of holes inthe gill plate). When the granules are dry they are allowed to fall intoa drum placed under the fluid bed. The fluid bed is constructed in sucha way that the overall dwelling time in the fluid bed is approximately2½% hours.

Step 5:

The drums containing the dry granules are placed upside down on top ofthe mill and the granules are gently milled using a screen, which willonly break the granules that are too long. After passing the mill, thegranules are allowed to fall into a drum.

Step 6:

Due to the fact that the milling process generates a small amount ofundersized granules, the granules are sieved using a Mogensen vibrationsieve. Granules, which pass the screen 0.8 mm, are discarded or can becollected for reprocessing stored in airtight, labelled containers.

Step 7:

200 kg of sieved granules are coated in a Kugel coater (fluid bedsystem) with a coating liquid consisting of ethyl cellulose dissolved inacetone.

In order to be able to determine the right amount of ethylcellulosenecessary to apply on the granules to get the desirable dissolution rateprofile, the surface area of the granules is measured prior to thecoating process. The prediction of the quantity of coating that isnecessary to apply on the granules has been developed based on the factthat there is a correlation between the amount of coating per surfacearea and the dissolution rate of the granules.

When the coating step was performed in a HKC 400 Hüttlin Kugel coaterand followed by production scale sieving, release characteristicsaccording to the invention, as measured as released % of total amount ofmesalazine or according to the first preferred aspect as defined by thesimilarity factor, was achieved when the amount of ethylcellulose wasadjusted to 0.13 mg/cm².

After finishing the coating process, the coated granules are loaded intoa drum for further processing.

Step 8:

After the coating process, the coated granules are sieved in a Prodimarotation sieve. Large lumps are discarded.

Step 9:

After sieving the batch of coated granules, they are divided into twodrums for purging with compressed air or nitrogen. The granules arepurged for 6-14 hours. This purging process is necessary to reduce theamount of residual solvent (acetone) in the coated granules.

This batch gave granulate with the following approximate composition:

mesalazine 94.3% Povidone 4.7% Ethylcellulose 1.0%

The granulate was subsequently filled into sachets.

The material of the sachets had the following composition:

Paper, claycoated 50 g/m² Polyethylene, low density 12 g/m² Aluminiumfoil 12 μm Polyethylene, low density 35 g/m²

For the present example 12 g/m² PE corresponds to 13 μm, and 35 g/m² PEcorresponds to 38 μm. The material had a grammage of 129 g/m². Thepermeability to water vapour was <0.05 g/m², 24 h, 25° C., 75% RH, andto O₂<0.05 ml/m², 24 h, atm, 23° C., 75% RH.

The sachets were folded around the filling tube of a filling/sealingstation, such that the paper was on the outside of the sachet, and thensealed lengthwise, with a low density polyethylene as a sealing layer.After forming the cross seal at the bottom the sachet is filled withgranulates, and then sealed again at the top and finally cut.

All citations are incorporated in their entirety by reference.

The invention claimed is:
 1. A pharmaceutical formulation suitable fororal administration and in the form of coated, flowable granulescomprising: 92 to 98% by weight of mesalazine or a pharmaceuticallyacceptable salt thereof; 2 to 8% by weight of polyvinylpyrrolidone; anda coating comprising ethylcellulose, the ratio of the weight of thecoating to the weight of the mesalazine or pharmaceutically acceptablesalt thereof being 0.7-3%; the coated, flowable granules being in asachet, capsule or blister package; wherein the coated granules, whensuspended in an aqueous buffer at pH 7.5, release the mesalazineaccording to a release profile in which: a) 5-25% of the total amount ofmesalazine or pharmaceutically acceptable salt thereof in the granulesis released after 15 min; b) 30-70% of the total amount of mesalazine orpharmaceutically acceptable salt thereof in the granules is releasedafter 90 min; and c) 75-100% of the total amount of mesalazine orpharmaceutically acceptable salt thereof in the granules is releasedafter 240 min; when measured in a model system using a USP Paddle System2 operated at 37° C. with stirring at 100 rpm.
 2. The formulation ofclaim 1, comprising 4 to 6% by weight of polyvinylpyrrolidone.
 3. Thepharmaceutical formulation of claim 1, having a similarity factor f2above 30 as compared to a standard formulation having in vitro releasecharacteristics such that a) 12% of the total amount of mesalazine inthe standard formulation is released after 15 min; b) 50% of the totalamount of mesalazine in the standard formulation is released after 90min; and c) 85% of the total amount of mesalazine in the standardformulation is released after 240 min; when measured in a model systemusing a USP Paddle System 2 operated at 37° C. with stirring at 100 rpm.4. The pharmaceutical formulation of claim 3, having a similarity factorf2 above 40 as compared to the standard formulation.
 5. Thepharmaceutical formulation of claim 3, having a similarity factor f2above 50 as compared to the standard formulation.
 6. The pharmaceuticalformulation of claim 1, consisting of mesalazine, polyvinylpyrrolidone,and coating.
 7. The pharmaceutical formulation of claim 1, provided in asachet comprising a total dosage amount of mesalazine or apharmaceutically acceptable salt thereof selected from the groupconsisting of 0.5 g, 1.0 g., 1.5 g., 2 g, 3 g, 4 g, 5 g, 6 g, 8 g, and10 g.
 8. The pharmaceutical formulation of claim 1, having in vitrorelease characteristics such that 40-60% of the total amount ofmesalazine or pharmaceutically acceptable salt thereof in theformulation is released after 90 min, when measured in a model systemusing a USP Paddle System 2 operated at 37° C. with stirring at 100 rpm.